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2qcn
From Proteopedia
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| - | [[Image:2qcn.jpg|left|200px]] | ||
| - | + | ==Covalent complex of the orotidine-5'-monophosphate decarboxylase domain of human UMP synthase with 6-iodo-UMP== | |
| - | + | <StructureSection load='2qcn' size='340' side='right'caption='[[2qcn]], [[Resolution|resolution]] 1.85Å' scene=''> | |
| - | + | == Structural highlights == | |
| - | + | <table><tr><td colspan='2'>[[2qcn]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QCN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2QCN FirstGlance]. <br> | |
| - | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=U5P:URIDINE-5-MONOPHOSPHATE'>U5P</scene></td></tr> | |
| - | + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2qcc|2qcc]], [[2qcd|2qcd]], [[2qce|2qce]], [[2qcf|2qcf]], [[2qcg|2qcg]], [[2qch|2qch]], [[2qcl|2qcl]], [[2qcm|2qcm]], [[2v30|2v30]], [[2jgy|2jgy]]</div></td></tr> | |
| - | + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">UMPS ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |
| - | + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Orotidine-5'-phosphate_decarboxylase Orotidine-5'-phosphate decarboxylase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.1.1.23 4.1.1.23] </span></td></tr> | |
| - | | | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2qcn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qcn OCA], [https://pdbe.org/2qcn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2qcn RCSB], [https://www.ebi.ac.uk/pdbsum/2qcn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2qcn ProSAT]</span></td></tr> |
| - | + | </table> | |
| - | + | == Disease == | |
| - | + | [[https://www.uniprot.org/uniprot/UMPS_HUMAN UMPS_HUMAN]] Defects in UMPS are the cause of orotic aciduria type 1 (ORAC1) [MIM:[https://omim.org/entry/258900 258900]]. A disorder of pyrimidine metabolism resulting in megaloblastic anemia and orotic acid crystalluria that is frequently associated with some degree of physical and mental retardation. A minority of cases have additional features, particularly congenital malformations and immune deficiencies.<ref>PMID:9042911</ref> | |
| - | + | == Evolutionary Conservation == | |
| - | + | [[Image:Consurf_key_small.gif|200px|right]] | |
| - | == | + | Check<jmol> |
| + | <jmolCheckbox> | ||
| + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/qc/2qcn_consurf.spt"</scriptWhenChecked> | ||
| + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | ||
| + | <text>to colour the structure by Evolutionary Conservation</text> | ||
| + | </jmolCheckbox> | ||
| + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2qcn ConSurf]. | ||
| + | <div style="clear:both"></div> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
UMP synthase (UMPS) catalyzes the last two steps of de novo pyrimidine nucleotide synthesis and is a potential cancer drug target. The C-terminal domain of UMPS is orotidine-5'-monophosphate decarboxylase (OMPD), a cofactor-less yet extremely efficient enzyme. Studies of OMPDs from micro-organisms led to the proposal of several noncovalent decarboxylation mechanisms via high-energy intermediates. We describe nine crystal structures of human OMPD in complex with substrate, product, and nucleotide inhibitors. Unexpectedly, simple compounds can replace the natural nucleotides and induce a closed conformation of OMPD, defining a tripartite catalytic site. The structures outline the requirements drugs must meet to maximize therapeutic effects and minimize cross-species activity. Chemical mimicry by iodide identified a CO(2) product binding site. Plasticity of catalytic residues and a covalent OMPD-UMP complex prompt a reevaluation of the prevailing decarboxylation mechanism in favor of covalent intermediates. This mechanism can also explain the observed catalytic promiscuity of OMPD. | UMP synthase (UMPS) catalyzes the last two steps of de novo pyrimidine nucleotide synthesis and is a potential cancer drug target. The C-terminal domain of UMPS is orotidine-5'-monophosphate decarboxylase (OMPD), a cofactor-less yet extremely efficient enzyme. Studies of OMPDs from micro-organisms led to the proposal of several noncovalent decarboxylation mechanisms via high-energy intermediates. We describe nine crystal structures of human OMPD in complex with substrate, product, and nucleotide inhibitors. Unexpectedly, simple compounds can replace the natural nucleotides and induce a closed conformation of OMPD, defining a tripartite catalytic site. The structures outline the requirements drugs must meet to maximize therapeutic effects and minimize cross-species activity. Chemical mimicry by iodide identified a CO(2) product binding site. Plasticity of catalytic residues and a covalent OMPD-UMP complex prompt a reevaluation of the prevailing decarboxylation mechanism in favor of covalent intermediates. This mechanism can also explain the observed catalytic promiscuity of OMPD. | ||
| - | + | Structures of the human orotidine-5'-monophosphate decarboxylase support a covalent mechanism and provide a framework for drug design.,Wittmann JG, Heinrich D, Gasow K, Frey A, Diederichsen U, Rudolph MG Structure. 2008 Jan;16(1):82-92. PMID:18184586<ref>PMID:18184586</ref> | |
| - | + | ||
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| + | <div class="pdbe-citations 2qcn" style="background-color:#fffaf0;"></div> | ||
| - | == | + | ==See Also== |
| - | + | *[[Phosphoribosyltransferase 3D structures|Phosphoribosyltransferase 3D structures]] | |
| - | [[Category: | + | *[[Uridine 5'-monophosphate synthase 3D structures|Uridine 5'-monophosphate synthase 3D structures]] |
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Human]] | ||
| + | [[Category: Large Structures]] | ||
[[Category: Orotidine-5'-phosphate decarboxylase]] | [[Category: Orotidine-5'-phosphate decarboxylase]] | ||
| - | + | [[Category: Rudolph, M]] | |
| - | [[Category: Rudolph, M | + | [[Category: Wittmann, J]] |
| - | [[Category: Wittmann, J | + | [[Category: Catalytic proficiency]] |
| - | [[Category: | + | [[Category: Decarboxylase]] |
| - | + | [[Category: Disease mutation]] | |
| - | [[Category: | + | [[Category: Glycosyltransferase]] |
| - | [[Category: | + | [[Category: Lyase]] |
| - | [[Category: | + | [[Category: Multifunctional enzyme]] |
| - | [[Category: | + | [[Category: Pyrimidine biosynthesis]] |
| - | [[Category: | + | [[Category: Transferase]] |
| - | [[Category: | + | [[Category: Ump synthase]] |
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| - | [[Category: | + | |
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Current revision
Covalent complex of the orotidine-5'-monophosphate decarboxylase domain of human UMP synthase with 6-iodo-UMP
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